The present application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created Nov. 15, 2013, is named “194_sequence_listing” and is 77,598 bytes in size.
I. Field of the Invention
The present invention relates to the fields of molecular biology and medicine. More specifically, there are methods and compositions involving RNA molecules with at least the functional properties of miR-34 and in some embodiments, enhanced characteristics related to miR-34 for the treatment of diseases and/or conditions. In some embodiments, RNA molecules that function as miR-34a or as miR-34c are provided in these contexts.
II. Background
In 2001, several groups used a cloning method to isolate and identify a large group of “microRNAs” (miRNAs) from C. elegans, Drosophila, and humans (Lau et al., 2001; Lee and Ambros, 2001; Lagos-Quintana et al., 2003).
Published human mature microRNA sequences, described in the database miRBase 15.0 (Griffths-Jones et al., 2006), range in size from 16-27 nucleotides in length and arise from longer precursors. The precursors form structures that fold back on themselves in self-complementary regions and are processed by the nuclease Dicer (in animals) or DCL1 (in plants) to generate the short double-stranded mature miRNA. One of the mature miRNA strands is incorporated into a complex of proteins and miRNA called the RNA-induced silencing complex (RISC). The miRNA guides the RISC complex to a target mRNA, which is then cleaved or translationally silenced, depending on the degree of sequence complementarity of the miRNA to its target mRNA. Currently, it is believed that perfect or nearly perfect complementarity leads to mRNA degradation, as is most commonly observed in plants. In contrast, imperfect base pairing, as is primarily found in animals, leads to translational silencing. However, recent data suggest additional complexity (Bagga et al., 2005; Lim et al., 2005), and mechanisms of gene silencing by miRNAs remain under intense study.
Studies have shown that changes in the expression levels of numerous miRNAs are associated with various cancers (reviewed in Calin and Croce, 2006; Esquela-Kerscher and Slack, 2006; Wiemer, 2007). miRNAs have also been implicated in regulating cell growth and cell and tissue differentiation—cellular processes that associated with the development of cancer.
The activity of a variety of miRNAs has been identified and analyzed. Although effective miRNA mimics have been identified previously in U.S. Patent Application Publication 20080050744, which is hereby incorporated by reference, there is a need for additional miRNA mimics that greatly improve one or more properties of the naturally occurring miRNA, particularly as these molecules move from the laboratory to the clinic.